The pan-FGFR inhibitor erdafitinib showed responses in more than one-third of patients with pretreated metastatic or unresectable FGFR alteration-positive urothelial carcinoma, according to findings from an ongoing open-label phase II study presented at the 2018 Genitourinary Cancers Symposium.

In the global trial, which examined 3 doses of erdafitinib, the objective response rate (ORR) across all regimens was 35% and the confirmed disease control rate (DCR) was 76%. Median progression-free survival (PFS) across all dosing cohorts was 5.1 months.

The highest rate of response occurred with continuous dosing of erdafitinib at 8 mg/day, with uptitration to 9 mg/day allowed. In this group (n = 59), the ORR was 42%, with a complete response in 5% and a partial response in 37% of patients. The DCR in this group was 81%, and the median duration of response was 5.4 months, with many responses ongoing. Fifty-seven percent of patients who received 8mg/day continuous dosing were still alive at 1 year.

"Erdafitinib is well-tolerated in patients with metastatic, surgically unresectable urothelial carcinoma and FGFR alterations, with a safety profile that allows continuous dosing," said lead investigator Yohann Loriot, MD, from the Institut Gustave Roussy, Villejuif Cedex, France. “Seventy-five percent of patients treated with 8 mg continuous erdafitinib had reduction in the sum of target lesion diameters, regardless of the kind of gene alterations.”

Overall, FGFR alterations have been found in approximately 20% to 30% of patients with urothelial carcinoma, with amplifications, mutations, and fusions in FGFR most commonly observed in the luminal cluster I subtype of urothelial carcinoma.

“Although, immunotherapy has improved outcomes in some patients, responses vary by subtype, and many patients with terminal cluster I subtype urothelial cancer may not benefit,” Loriot said. “Treatment with an FGFR inhibitor may be particularly appropriate in patients with luminal cluster I subtype, in which FGFR alterations are common and in which PD-1 and PD-L1 inhibitors may be less effective.”

In the phase II study, patients were randomized to 28-day cycles of oral erdafitinib at 6 mg/day continuous dosing or 10 mg/day intermittent (7 days on/7 days off dosing). A third cohort looking at 8 mg/day continuous dosing was subsequently opened, following an interim analysis. All patients in the trial had FGFR2/FGFR3 mutations or fusions and had progressed during or following at least 1 line of prior systemic chemotherapy or within 12 months of receiving neoadjuvant or adjuvant chemotherapy.

At an interim analysis, enrollment in the intermittent dosing group was stopped, after 33 patients were treated. Enrollment continued for the 6 mg/day continuous dosing regimen (n = 78). Based on pharmacokinetic and pharmacodynamics modeling and the clinical safety of 6 mg/day, the investigators decided to proceed with an 8-mg/day continuous dosing regimen; this arm is ongoing until 100 patients have been enrolled.

Patients in the 8 mg/day arm could be further uptitrated to 9 mg/day, if they had not reached a target serum phosphate level ≥5.5 mg/dL by day 14 and if they had no treatment-related adverse events (TRAEs). Data from the first 59 patients enrolled in this arm were presented. “These early results suggest that continuous dosing with uptitration is tolerable and may result in improved clinical activity,” Loriot said.

In the 8 mg/day group, the median age of patients was 67, and 93% of patients had an ECOG performance status of 0 or 1. Overall, 46% of patients had received 1 prior therapy and 31% were treated with 2 prior regimens, which included immunotherapy for 19% of patients. Seventy-six percent of patients had visceral metastases, and the creatinine clearance rate was 40 to 59 mL/min for 54% of patients.

The ORR was 35% and 24% in the continuous 6 mg/day group and the 10 mg/day intermittent group, respectively, with DCRs of 73% in each group. The median PFS was 5.1 for the continuous 6 mg/day dose and 4.0 months for the intermittent 10 mg/day dose. The 1-year overall survival rates were 32% and 31%, for the continuous and intermittent groups, respectively.

In the safety analysis, erdafitinib was well tolerated with no treatment-related deaths. Ten percent discontinued treatment due to TRAEs. In 96 patients treated with the 8 mg/day continuous dose, the most common TRAEs of any grade were hyperphosphatemia (69%), stomatitis (47%), diarrhea (42%), dry mouth (42%), and dysgeusia (33%). The most common grade ≥3 TRAEs were stomatitis (8%), asthenia (3%), and diarrhea (3%).

A phase III study is comparing erdafitinib at 8 mg/day with vinflunine, docetaxel, or pembrolizumab for patients with advanced urothelial cancer with selected FGFR gene alterations. The open-label trial has an estimated enrollment of 630 participants, with a planned primary completion date of November 2020. The primary endpoint of the study is overall survival (NCT03390504).